Design and Rationale of a Phase 3 Trial for Admilparant (BMS-986278), an Oral Lysophosphatidic Acid Receptor 1 Antagonist, in Patients With Progressive Pulmonary Fibrosis: ALOFT-PPF

RATIONALE: Progressive pulmonary fibrosis (PPF) encompasses a group of heterogenous interstitial lung diseases (ILD) characterized by fibrosis with a progressive clinical course. Admilparant (BMS-986278), an oral lysophosphatidic acid receptor 1 antagonist, has shown positive results in a phase 2 trial including patients with PPF (Corte, 2024, AJRCCM); 60 mg twice daily (BID) was well tolerated and associated with reduced lung function decline over 26 weeks compared with placebo, though asymptomatic hypotension was observed in 13/42 (31.0%) patients. ALOFT-PPF is a phase 3 trial which aims to further investigate admilparant in patients with PPF, currently enrolling across >30 countries with >400 clinical trial sites. METHODS: ALOFT-PPF, a phase 3, multicenter, randomized, double-blind, placebo-controlled clinical trial, will randomize adults (≥21 years) with PPF to receive admilparant 60 or 120 mg or placebo (1:1:1) orally, BID for ≥52 weeks. Inclusion criteria include a diagnosis of ILD with features of progression within 24 months of screening, >10% fibrosis on high-resolution computed tomography, percent of predicted forced vital capacity (ppFVC) ≥40%, and percent of predicted diffusing capacity of the lung for carbon monoxide ≥25%. Background treatment (antifibrotic and certain immunosuppressive therapies) is allowed. Randomization will be stratified by background therapy (antifibrotic and/or immunosuppressive therapy) and/or usual interstitial pneumonia pattern. ALOFT-PPF includes a 2-cohort trial design to assess the safety of admilparant 120 mg (Figure). Cohort 1 (n∼60), a single-blind design, will enroll patients with PPF to evaluate the safety and tolerability of admilparant; the primary endpoint is the number of spontaneous syncopal episodes (admilparant 120 mg vs placebo) after 4 weeks of treatment. Based on the evaluation of syncopal episodes together with ALOFT-IPF (NCT06003426) from cohort 1, cohort 2 (n∼1032) will be initiated as a parallel, registrational, double-blind design to evaluate the efficacy, safety, and tolerability of admilparant compared with placebo. The primary endpoint for cohort 2 is absolute change in FVC from baseline to week 52. Key secondary endpoints include time to disease progression (absolute ppFVC decline ≥10%, acute exacerbation of pulmonary fibrosis, respiratory-related hospitalizations, and all-cause mortality), change from baseline to week 52 in the Living with Pulmonary Fibrosis (L-PF) questionnaire cough domain score, and L-PF dyspnea domain score (Figure). RESULTS: Enrollment into ALOFT-PPF started October 25, 2023, and will continue until target enrollment is reached. CONCLUSIONS: ALOFT-PPF will determine the effect of admilparant on safety, FVC, disease progression and quality-of-life over ≥52 weeks in patients with PPF. Trial registration number:NCT06025578